The present invention relates to a novel process for preparing known spirocyclic tetronic acid derivatives.
The multi-step synthesis of spirocyclic tetronic acid derivatives is known (EP-A-528 156).
It has now been found that compounds of the formula (I) 
in which
X represents alkyl, halogen, alkoxy or halogenoalkyl,
Y represents hydrogen, alkyl, halogen, alkoxy or halogenoalkyl,
Z represents alkyl, halogen or alkoxy,
n represents a number from 0 to 3, or the radicals X and Z together with the phenyl radical to which they are attached form the naphthalene radical of the formula 
in which Y is as defined above,
A represents an in each case optionally substituted radical from the group consisting of alkyl, alkenyl, alkoxyalkyl, polyalkoxyalkyl and alkylthioalkyl, represents in each case saturated or unsaturated and optionally substituted cycloalkyl or heterocyclyl or represents in each case optionally halogen-, alkyl-, halogenoalkyl-, alkoxy-, halogenoalkoxy-, cyano- or nitro-substituted aryl, arylalkyl or hetaryl,
B represents alkyl or alkoxyalkyl or
A and B together with the carbon atom to which they are attached represent a saturated or unsaturated, optionally substituted carbocycle or heterocycle,
R1 represents in each case optionally halogen-substituted alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, alkylthioalkyl, polyalkoxyalkyl or optionally substituted cycloalkyl which may be interrupted by heteroatoms, represents optionally substituted phenyl or phenoxy, optionally substituted phenylalkyl or phenylalkyloxy, substituted hetaryl, substituted phenoxyalkyl or substituted hetaryloxyalkyl,
and the stereo- and enantiomerically pure forms of compounds of the formula (I) are obtained when compounds of the formula (II) 
in which
X, Y, Z, n, A and B are each as defined above and
R8 represents alkyl
are reacted with a base and compounds of the formula (III) 
in which
R1 is as defined above and
Hal represents halogen, in particular chlorine or bromine,
if appropriate in the presence of a diluent.
Using the process according to the invention, it is surprisingly possible to prepare the abovementioned compounds in a simpler manner in a one-pot process, without isolation of the intermediates, in higher purity and with better yields.
In the general formulae (I), (II) and (III), the substituents
X preferably represents C1-C6-alkyl, halogen, C1-C6-alkoxy or C1-C3-halogenoalkyl,
Y preferably represents hydrogen, C1-C6-alkyl, halogen, C1-C6-alkoxy or C1-C3-halogenoalkyl,
Z preferably represents C1-C6-alkyl, halogen or C1-C6-alkoxy,
n preferably represents a number from 0 to 3,
xe2x80x83or the radicals X and Z together with the phenyl radical to which they are attached form the naphthalene radical of the formula 
in which Y is defined as above,
A preferably represents in each case optionally halogen-substituted C1-C12-alkyl, C2-C8-alkenyl, C1-C10-alkoxy-C1-C8-alkyl, represents optionally halogen-, C1-C6-alkyl- or C1-C6-alkoxy-substituted C3-C8-cycloalkyl, in which optionally one or two not directly adjacent methylene groups are replaced by oxygen and/or sulphur or represents in each case optionally halogen-, C1-C6-alkyl-, C1-C6-halogenoalkyl-, C1-C6-alkoxy-, C1-C6-halogenoalkoxy-, cyano- or nitro-substituted phenyl or phenyl-C1-C6-alkyl,
B preferably represents C1-C12-alkyl or C1-C8-alkoxy-C1-C6-alkyl or
A, B and the carbon atom to which they are attached preferably represent C5-C10-cycloalkyl or C5-C10-cycloalkenyl in which optionally one methylene group is replaced by oxygen or sulphur and which are optionally substituted by C1-C8-alkyl, C3-C10-cycloalkyl, C1-C8-halogenoalkyl, C1-C8-alkoxy, C1-C8-alkylthio, halogen or phenyl or
A, B and the carbon to which they are attached preferably represent C5-C8-cycloalkyl or C5-C8-cycloalkenyl in which two carbon atoms are attached to one another by in each case optionally C1-C6-alkyl-, C1-C6-alkoxy- or halogen-substituted C3-C6-alkanediyl, C3-C6-alkenediyl or C4-C6-alkanedienediyl in which in each case optionally one methylene group is replaced by oxygen or sulphur,
R8 preferably represents C1-C6-alkyl,
Hal preferably represents chlorine or bromine,
R1 preferably represents in each case optionally halogen-substituted C1-C20-alkyl, C1-C20-alkoxy, C2-C20-alkenyl, C3-C10-alkenyloxy, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkylthio-C1-C8-alkyl, optionally C1-C6-alkyl-, C1-C6-alkoxy-, fluorine- or chlorine-substituted cycloalkyl having 3 to 8 ring atoms which may be interrupted by oxygen and/or sulphur atoms,
xe2x80x83preferably represents in each case optionally halogen-, nitro-, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-halogenoalkyl- or C1-C6-halogenoalkoxy-substituted phenyl or phenoxy;
xe2x80x83preferably represents in each case optionally halogen-, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-halogenoalkyl-, C1-C6-halogenoalkoxy-substituted phenyl-C1-C6-alkyl or phenyl-C1-C4-alkyloxy,
xe2x80x83preferably represents optionally halogen- or C1-C6-alkyl-substituted hetaryl,
xe2x80x83preferably represents optionally halogen- or C1-C6-alkyl-substituted phenoxy-C1-C6-alkyl,
xe2x80x83preferably represents optionally halogen-, amino- or C1-C6-alkyl-substituted hetaryloxy-C1-C6-alkyl.
In the general formulae (I), (II) and (III), the substituents
X particularly preferably represents C1-C4-alkyl, fluorine, chlorine, bromine, C1-C4-alkoxy or C1-C2-halogenoalkyl,
Y particularly preferably represents hydrogen, C1-C4-alkyl, fluorine, chlorine, bromine, C1-C4-alkoxy or C1-C2-halogenoalkyl,
Z particularly preferably represents C1-C4-alkyl, fluorine, chlorine, bromine or C1-C4-alkoxy,
n particularly preferably represents a number from 0 to 2,
A, B and the carbon atom to which they are attached particularly preferably represent C5-C8-cycloalkyl in which in each case optionally one methylene group is replaced by oxygen or sulphur and which is optionally substituted by C1-C6-alkyl, C1-C3-halogenoalkyl, C1-C6-alkoxy, fluorine or chlorine, or
A, B and the carbon atom to which they are attached particularly preferably represent C5-C6-cycloalkyl in which two carbon atoms are attached to one another by in each case optionally C1-C4-alkyl-, C1-C4-alkoxy-, fluorine-, chlorine- or bromine-substituted C3-C5-alkanediyl, C3-C5-alkenediyl, in which in each case optionally one methylene group is replaced by oxygen or sulphur, or attached to one another by butadienediyl,
R8 particularly preferably represents C1-C4-alkyl,
Hal particularly preferably represents chlorine or bromine,
R1 particularly preferably represents in each case optionally fluorine- or chlorine-substituted C1-C16-alkyl, C1-C16-alkoxy, C3-C6-alkenyloxy, C2-C16-alkenyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkylthio-C1-C4-alkyl, optionally methyl-, ethyl-, methoxy-, fluorine- or chlorine-substituted cycloalkyl having 3 to 7 ring atoms which may be interrupted by 1 or 2 oxygen and/or sulphur atoms,
xe2x80x83represents in each case optionally fluorine-, chlorine-, bromine-, nitro-, C1-C4-alkyl-, C1-C4-alkoxy-, C1-C3-halogenoalkyl- or C1-C3-halogenoalkoxy-substituted phenyl, phenoxy or benzyloxy,
xe2x80x83represents optionally halogen- or C1-C6-alkyl-substituted hetaryl.
In the general formulae (I), (II) and (III), the substituents
X very particularly preferably represents methyl, ethyl, propyl, i-propyl, fluorine, chlorine, bromine, methoxy, ethoxy or trifluoromethyl,
Y very particularly preferably represents hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, tert-butyl, fluorine, chlorine, bromine, methoxy, ethoxy or trifluoromethyl,
Z very particularly preferably represents methyl, ethyl, i-propyl, butyl, i-butyl, tert-butyl, fluorine, chlorine, bromine, methoxy or ethoxy,
n very particularly preferably represents the number 0 to 1,
A, B and the carbon atom to which they are attached very particularly preferably represent C3-C8-cycloalkyl in which in each case optionally one methylene group is replaced by oxygen or sulphur and which is optionally substituted by methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, iso-propoxy, butoxy or iso-butoxy,
R8 very particularly preferably represents methyl, ethyl, propyl or iso-propyl,
Hal very particularly preferably represents chlorine or bromine,
R1 very particularly preferably represents in each case optionally fluorine- or chlorine-substituted C1-C14-alkyl, C1-C10-alkoxy, C2-C14-alkenyl, C3-C6-alkenyloxy, C1-C4-alkoxy-C1-C2-alkyl, C1-C4-alkylthio-C1-C2-alkyl or cycloalkyl having 3 to 6 ring atoms which may be interrupted by 1or 2 oxygen and/or sulphur atoms,
xe2x80x83represents in each case optionally fluorine-, chlorine-, bromine-, methyl-, ethyl-, propyl-, i-propyl-, methoxy-, ethoxy-, trifluoromethyl-, trifluoromethoxy-, nitro-substituted phenyl, phenoxy or benzyloxy;
xe2x80x83represents optionally chlorine-, methyl- or ethyl-substituted pyridyl.
A very particularly preferred compound of the formula (I) is the compound of the formula (Ia) 
which is obtained by reacting the compound of the formula (IIa) 
with NaOH and the compound of the formula (IIIa) 
A further very particularly preferred compound of the formula (I) is the compound of the formula (Ib) 
which is obtained by reacting the compound of the formula (IIb) 
with NaOH and the compound of the formula (IIIb) 
Suitable bases (deprotonating agents) for the ring-closure reaction are all customary proton acceptors. Preference is given to using alkali metal and alkaline earth metal oxides, hydroxides and carbonates, such as sodium hydroxide, potassium hydroxide, magnesium oxide, calcium oxide, sodium carbonate, potassium carbonate and calcium carbonate, which can also be used in the presence of phase-transfer catalysts, such as, for example, triethylbenzylammonium chloride, tetrabutylammonium bromide, Adogen 464 (methyltrialkyl-(C8-C10)-ammonium chloride) or TDA 1 (tris-(methoxyethoxyethyl)-amine). It is furthermore possible to use alkali metals such as sodium or potassium. Also suitable are alkali metal and alkaline earth metal amides and hydrides, such as sodium amide, sodium hydride and calcium hydride, and furthermore also alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, or else tertiary amines, such as diazabicyclooctane (DABCO), diazabicycloundecene (DBU), diazabicyclononene (DBN) and Hxc3xcnig base.
Suitable diluents for the ring-closure reaction are all solvents which are inert to the base that is used. Preference is given to using hydrocarbons, such as benzine, benzene, toluene, xylene and tetraline, furthermore halogenated hydrocarbons, such as methyl chloride, chlorobenzene and o-dichlorobenzene, moreover ethers, such as diethyl ether, methyl tert-butyl ether, tert-amyl ether, tetrahydrofuran and dioxane, additionally strongly polar solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulphoxide and sulpholane.
After the ring-closure reaction has taken place, the acid halide is added to the reaction solution.
To scavenge residual hydrogen chloride from the acid chloride preparation, it is possible to add small amounts of customary acid acceptors. Preference is given to using tertiary amines, such as triethylamine, pyridine, diazabicyclooctane (DABCO), diazabicycloundecene (DBU), diazabicyclononene (DBN), Hxc3xcnig base and N,N-dimethylaniline, furthermore alkaline earth metal oxides, such as magnesium oxide and calcium oxide, moreover alkali metal and alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate and calcium carbonate.
In the process according to the invention, the reaction temperatures can be varied within a relatively wide range. In general, the process is carried out at temperatures between xe2x88x9220xc2x0 C. and +200xc2x0 C., preferably between 0xc2x0 C. and 150xc2x0 C.
The reaction is generally carried out under reduced pressure, preferably in a range of 50-500 mbar.
When carrying out the process according to the invention, the reaction components of the formulae (II) and (III) and the deprotonating bases are generally employed in approximately equimolar amounts. However, it is also possible to use a relatively large excess (up to 5 mol, preferably up to 2 mol) of one or the other component.
The starting materials of the formula (II) are known. Their preparation is described in EP-A-647 637. The carbonyl halides of the formula (III) are likewise known. They are commercially available or can be prepared by generally customary processes of organic chemistry.